Identification

Name
Brivaracetam
Accession Number
DB05541
Type
Small Molecule
Groups
Approved, Investigational
Description

Brivaracetam is a racetam derivative of levetiracetam used in the treatment of partial-onset seizures. Brivaracetam binds SV2A with 20 times higher affinity than levetiracetam [2]. It is available under the brand name Briviact made by UCB. Briviact received FDA approval on February 19, 2016 [7].

Structure
Thumb
Synonyms
Not Available
External IDs
UCB 34714 / UCB-34714
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
BriviactTablet, film coated50 mgOralUcb Pharma Sa2016-01-14Not applicableEu
BriviactTablet, film coated10 mgOralUcb Pharma Sa2016-01-14Not applicableEu
BriviactTablet, film coated25 mgOralUcb Pharma Sa2016-01-14Not applicableEu
BriviactTablet, film coated100 mgOralUcb Pharma Sa2016-01-14Not applicableEu
BriviactSolution10 mg/1mLOralUcb Inc2016-05-12Not applicableUs
BriviactTablet, film coated25 mgOralUcb Pharma Sa2016-01-14Not applicableEu
BriviactTablet, film coated100 mgOralUcb Pharma Sa2016-01-14Not applicableEu
BriviactTablet, film coated75 mg/1OralUcb Inc2016-05-12Not applicableUs
BriviactTablet, film coated10 mgOralUcb Pharma Sa2016-01-14Not applicableEu
BriviactTablet, film coated75 mgOralUcb Pharma Sa2016-01-14Not applicableEu
International/Other Brands
Rikelta (UCB)
Categories
UNII
U863JGG2IA
CAS number
357336-20-0
Weight
Average: 212.2887
Monoisotopic: 212.152477894
Chemical Formula
C11H20N2O2
InChI Key
MSYKRHVOOPPJKU-BDAKNGLRSA-N
InChI
InChI=1S/C11H20N2O2/c1-3-5-8-6-10(14)13(7-8)9(4-2)11(12)15/h8-9H,3-7H2,1-2H3,(H2,12,15)/t8-,9+/m1/s1
IUPAC Name
(2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide
SMILES
CCC[C@H]1CN([C@@H](CC)C(N)=O)C(=O)C1

Pharmacology

Indication

Used as adjunctive therapy for partial-onset seizures in patients 16 years of age or older.

Associated Conditions
Pharmacodynamics

Brivaracetam binds SV2A with high affinity [2]. SV2A is known to play a role in epileptogenesis through modulation of synaptic GABA release [3]. It is thought that brivaracetam exerts its anti-epileptogenic effects through its binding to SV2A. Brivaracetam is also known to inhibit Na+ channels which may also contribute to its anti-epileptogenic action [4].

Mechanism of action

The precise mechanism of brivaracetam's anti-epileptogenic activity is unknown.

TargetActionsOrganism
ASynaptic vesicle glycoprotein 2A
unknown
Human
ASodium channel protein
inhibitor
Human
Absorption

Nearly 100% oral bioavailability [1].

Volume of distribution

0.5L/kg [Label].

Protein binding

<20% bound to plasma proteins [Label].

Metabolism

Primarily metabolized by hydrolysis of the acetamide moeity to form a carboxylic acid metabolite [6]. Another metabolite is created via oxidation of the propyl side chain by CYP2C8 as well as CYP3A4, CYP2C19, and CYP2B6. Some conjugation with glucuronic acid and taurine account for a small amount of metabolism.

Route of elimination

>95% excreted in urine with <10% of the parent compound unchanged. <1% excreted in feces [Label].

Half life

7-8h [1].

Clearance

CL/F of 0.7-1.07 mL/min kg [5]. Clearance is primarily metabolic with less than 10% of the parent drug excreted unchanged.

Toxicity

No carcinogenesis or fertility impairment found. Overdose is associated with somnolence and dizziness [Label].

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Interacting Gene/EnzymeAllele nameGenotype(s)Defining Change(s)Type(s)DescriptionDetails
Cytochrome P450 2C19CYP2C19*2ANot Available681G>AEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C19CYP2C19*2BNot Available681G>AEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C19CYP2C19*3Not Available636G>AEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C19CYP2C19*4Not Available1A>GEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C19CYP2C19*5Not Available1297C>TEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C19CYP2C19*6Not Available395G>AEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C19CYP2C19*7Not Available19294T>AEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C19CYP2C19*22Not Available557G>C / 991A>GEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2C19CYP2C19*24Not Available99C>T / 991A>G  … show all Effect InferredPoor drug metabolizer.Details
Cytochrome P450 2C19CYP2C19*35Not Available12662A>GEffect InferredPoor drug metabolizer.Details

Interactions

Drug Interactions
DrugInteraction
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Brivaracetam.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of adverse effects can be increased when Brivaracetam is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3-isobutyl-1-methyl-7H-xanthineBrivaracetam may increase the excretion rate of 3-isobutyl-1-methyl-7H-xanthine which could result in a lower serum level and potentially a reduction in efficacy.
3,4-MethylenedioxyamphetamineThe risk or severity of adverse effects can be increased when 3,4-Methylenedioxyamphetamine is combined with Brivaracetam.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Brivaracetam.
4-MethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Methoxyamphetamine is combined with Brivaracetam.
5-methoxy-N,N-dimethyltryptamineThe risk or severity of adverse effects can be increased when Brivaracetam is combined with 5-methoxy-N,N-dimethyltryptamine.
6-O-benzylguanineBrivaracetam may increase the excretion rate of 6-O-benzylguanine which could result in a lower serum level and potentially a reduction in efficacy.
7-DeazaguanineBrivaracetam may increase the excretion rate of 7-Deazaguanine which could result in a lower serum level and potentially a reduction in efficacy.
7-NitroindazoleThe risk or severity of adverse effects can be increased when 7-Nitroindazole is combined with Brivaracetam.
Food Interactions
Not Available

References

General References
  1. Rolan P, Sargentini-Maier ML, Pigeolet E, Stockis A: The pharmacokinetics, CNS pharmacodynamics and adverse event profile of brivaracetam after multiple increasing oral doses in healthy men. Br J Clin Pharmacol. 2008 Jul;66(1):71-5. doi: 10.1111/j.1365-2125.2008.03158.x. Epub 2008 Mar 13. [PubMed:18341673]
  2. Gillard M, Fuks B, Leclercq K, Matagne A: Binding characteristics of brivaracetam, a selective, high affinity SV2A ligand in rat, mouse and human brain: relationship to anti-convulsant properties. Eur J Pharmacol. 2011 Aug 16;664(1-3):36-44. doi: 10.1016/j.ejphar.2011.04.064. Epub 2011 May 8. [PubMed:21575627]
  3. Tokudome K, Okumura T, Shimizu S, Mashimo T, Takizawa A, Serikawa T, Terada R, Ishihara S, Kunisawa N, Sasa M, Ohno Y: Synaptic vesicle glycoprotein 2A (SV2A) regulates kindling epileptogenesis via GABAergic neurotransmission. Sci Rep. 2016 Jun 6;6:27420. doi: 10.1038/srep27420. [PubMed:27265781]
  4. Zona C, Pieri M, Carunchio I, Curcio L, Klitgaard H, Margineanu DG: Brivaracetam (ucb 34714) inhibits Na(+) current in rat cortical neurons in culture. Epilepsy Res. 2010 Jan;88(1):46-54. doi: 10.1016/j.eplepsyres.2009.09.024. Epub 2009 Nov 13. [PubMed:19914041]
  5. Sargentini-Maier ML, Rolan P, Connell J, Tytgat D, Jacobs T, Pigeolet E, Riethuisen JM, Stockis A: The pharmacokinetics, CNS pharmacodynamics and adverse event profile of brivaracetam after single increasing oral doses in healthy males. Br J Clin Pharmacol. 2007 Jun;63(6):680-8. Epub 2007 Jan 12. [PubMed:17223857]
  6. Sargentini-Maier ML, Espie P, Coquette A, Stockis A: Pharmacokinetics and metabolism of 14C-brivaracetam, a novel SV2A ligand, in healthy subjects. Drug Metab Dispos. 2008 Jan;36(1):36-45. Epub 2007 Oct 1. [PubMed:17908923]
  7. Briviact FDA Approval [Link]
External Links
KEGG Drug
D08879
PubChem Compound
9837243
PubChem Substance
347827736
ChemSpider
8012964
BindingDB
50422531
ChEBI
133013
ChEMBL
CHEMBL607400
PharmGKB
PA166153491
Wikipedia
Brivaracetam
ATC Codes
N03AX23 — Brivaracetam
AHFS Codes
  • 28:12.92 — Miscellaneous Anticonvulsants
FDA label
Download (1.46 MB)
MSDS
Download (170 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceEpilepsies1
1CompletedOtherHealthy Volunteers2
1CompletedTreatmentEpilepsies1
1RecruitingBasic ScienceEpilepsies1
2CompletedTreatmentEpilepsies4
2CompletedTreatmentEpilepsy, Localization Related1
2CompletedTreatmentPostherpetic Neuralgia1
2RecruitingTreatmentEpilepsies1
2TerminatedTreatmentNonconvulsive Electrographic Seizures1
2, 3Not Yet RecruitingTreatmentElectroencephalographic Neonatal Seizures1
3Active Not RecruitingTreatmentEpilepsies2
3CompletedTreatmentEpilepsies9
3CompletedTreatmentUnverricht-Lundborg Disease1
3Enrolling by InvitationTreatmentEpilepsies1
3Enrolling by InvitationTreatmentEpilepsies / Partial Seizures With or Without Secondary Generalization1
3Not Yet RecruitingTreatmentEpilepsies / Partial Seizures With or Without Secondary Generalization1
3RecruitingTreatmentEpilepsies / Partial Seizures With or Without Secondary Generalization1
3TerminatedTreatmentEpilepsies2
Not AvailableAvailableNot AvailableEpilepsies1
Not AvailableNot Yet RecruitingNot AvailableAntiepileptics and Antiparkinsonism Drugs Causing Adverse Effects in Therapeutic Use / Epilepsies1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, solutionIntravenous10 mg/ml
Injection, suspensionIntravenous50 mg/5mL
SolutionOral10 mg/ml
SolutionOral10 mg/1mL
Tablet, film coatedOral10 mg
Tablet, film coatedOral10 mg/1
Tablet, film coatedOral100 mg
Tablet, film coatedOral100 mg/1
Tablet, film coatedOral25 mg/1
Tablet, film coatedOral25 mg
Tablet, film coatedOral50 mg
Tablet, film coatedOral50 mg/1
Tablet, film coatedOral75 mg/1
Tablet, film coatedOral75 mg
SolutionIntravenous10 mg
SolutionOral10 mg
TabletOral10 mg
TabletOral100 mg
TabletOral25 mg
TabletOral50 mg
TabletOral75 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6911461No2005-06-282021-02-21Us
US6784197No2004-08-312021-02-21Us
US8492416No2013-07-232021-02-21Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility46.8 mg/mLALOGPS
logP0.86ALOGPS
logP0.66ChemAxon
logS-0.66ALOGPS
pKa (Strongest Acidic)16.29ChemAxon
pKa (Strongest Basic)-0.57ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area63.4 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity57.75 m3·mol-1ChemAxon
Polarizability23.77 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9904
Blood Brain Barrier+0.9812
Caco-2 permeable-0.5912
P-glycoprotein substrateSubstrate0.5307
P-glycoprotein inhibitor IInhibitor0.5318
P-glycoprotein inhibitor IINon-inhibitor0.7691
Renal organic cation transporterNon-inhibitor0.766
CYP450 2C9 substrateNon-substrate0.9026
CYP450 2D6 substrateNon-substrate0.8221
CYP450 3A4 substrateSubstrate0.5486
CYP450 1A2 substrateNon-inhibitor0.9103
CYP450 2C9 inhibitorNon-inhibitor0.7784
CYP450 2D6 inhibitorNon-inhibitor0.9115
CYP450 2C19 inhibitorNon-inhibitor0.8035
CYP450 3A4 inhibitorNon-inhibitor0.9584
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.953
Ames testNon AMES toxic0.8836
CarcinogenicityNon-carcinogens0.8866
BiodegradationNot ready biodegradable0.9479
Rat acute toxicity2.2355 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9434
hERG inhibition (predictor II)Non-inhibitor0.8922
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as alpha amino acids and derivatives. These are amino acids in which the amino group is attached to the carbon atom immediately adjacent to the carboxylate group (alpha carbon), or a derivative thereof.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Alpha amino acids and derivatives
Alternative Parents
Pyrrolidine-2-ones / N-alkylpyrrolidines / Fatty amides / Tertiary carboxylic acid amides / Primary carboxylic acid amides / Lactams / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compounds / Organic oxides
show 2 more
Substituents
Alpha-amino acid or derivatives / Fatty amide / Pyrrolidone / 2-pyrrolidone / Fatty acyl / N-alkylpyrrolidine / Pyrrolidine / Tertiary carboxylic acid amide / Carboxamide group / Lactam
show 12 more
Molecular Framework
Aliphatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Unknown
General Function
Transmembrane transporter activity
Specific Function
Plays a role in the control of regulated secretion in neural and endocrine cells, enhancing selectively low-frequency neurotransmission. Positively regulates vesicle fusion by maintaining the readi...
Gene Name
SV2A
Uniprot ID
Q7L0J3
Uniprot Name
Synaptic vesicle glycoprotein 2A
Molecular Weight
82694.665 Da
Kind
Protein group
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Voltage-gated sodium channel activity
Specific Function
Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a...

Components:
References
  1. Zona C, Pieri M, Carunchio I, Curcio L, Klitgaard H, Margineanu DG: Brivaracetam (ucb 34714) inhibits Na(+) current in rat cortical neurons in culture. Epilepsy Res. 2010 Jan;88(1):46-54. doi: 10.1016/j.eplepsyres.2009.09.024. Epub 2009 Nov 13. [PubMed:19914041]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Sargentini-Maier ML, Espie P, Coquette A, Stockis A: Pharmacokinetics and metabolism of 14C-brivaracetam, a novel SV2A ligand, in healthy subjects. Drug Metab Dispos. 2008 Jan;36(1):36-45. Epub 2007 Oct 1. [PubMed:17908923]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. Sargentini-Maier ML, Espie P, Coquette A, Stockis A: Pharmacokinetics and metabolism of 14C-brivaracetam, a novel SV2A ligand, in healthy subjects. Drug Metab Dispos. 2008 Jan;36(1):36-45. Epub 2007 Oct 1. [PubMed:17908923]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. Sargentini-Maier ML, Espie P, Coquette A, Stockis A: Pharmacokinetics and metabolism of 14C-brivaracetam, a novel SV2A ligand, in healthy subjects. Drug Metab Dispos. 2008 Jan;36(1):36-45. Epub 2007 Oct 1. [PubMed:17908923]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Brivaracetam FDA Label [File]

Drug created on November 18, 2007 11:25 / Updated on November 16, 2018 11:22